Pharmaceutical oxaliplatinum preparation for parenteral administration and method for obtaining same

ABSTRACT

The present invention relates to a stable pharmaceutical preparation of oxaliplatin for parenteral administration, in which the oxaliplatin is in solution in a solvent at a concentration of at least 7 mg/ml, which has been subjected to an operation of wet heat treatment with steam in the saturation state and under pressure at a high temperature not exceeding 110° C. It also relates to the method for the production thereof.

This application is the U.S. national phase of international applicationPCT/CH01/00708 filed 12 Dec. 2001 which designated the U.S.

The present invention relates to a pharmaceutical preparation ofoxaliplatin, for parenteral administration, intended to be infused orinjected. It also relates to a method for obtaining said preparation.

Oxaliplatin (INN, also called I-OHP), a complex derivative of platinum(CAS RN: 61825-94-3) described by Kidani et al. in J. Med. Chem., 1978,21, 1315, is an antineoplastic agent used intravenously mostparticularly in the treatment of metastatic colorectal cancer.

Oxaliplatin, in its pure active substance form, is known to be slightlywater-soluble, relatively insoluble in methanol and virtually insolublein ethanol and acetone. More precisely, the maximum solubility ofoxaliplatin at saturation in water at 37° C. is 7.9 mg/ml and is 6 mg/mlat 20° C.

Currently, it is used in the hospital environment in a lyophilized formand the liquid preparation thereof is reconstituted using a glucosesolution just before it is administered, generally as an infusion ofshort duration.

In order to provide hospital personnel with the great advantage of,firstly, no longer having to handle a cytotoxic powder or cake duringthe reconstitution of the pharmaceutical preparation and, secondly,avoiding any risk of mistakenly using a reconstituting solutioncontaining chloride ions, such as a sodium chloride solutionconventionally used in this kind of operation, the serious consequenceof which is to decompose the metal complex, several liquid preparationsof oxaliplatin, ready to be administered parenterally by infusion, havealready been proposed.

Thus, Ibrahim et al. have described, in WO 96/04904, a pharmaceuticallystable preparation of oxaliplatin, ready to be administered parenterallyby infusion. This preparation, which has undergone successive operationsof clarifying filtration and then of aseptic filtration, consists of anaqueous solution of oxaliplatin at a concentration of approximately 2mg/ml which contains no other adjuvants.

Mauvernay has described, in WO 00/21527, that this type ofpharmaceutical preparation in which the oxaliplatin is at aconcentration of approximately 2 mg/ml can advantageously be conservedand transported in a flexible infusion bag in order to simplify evenfurther its handling during its administration to a patient. It isindicated, in that document, that the chosen material constituting thisflexible bag is able to withstand the high temperatures applied duringsterilization operations in an autoclave.

Anderson et al. have described, in WO 99/43355, two types of liquidformulation containing oxaliplatin. In the first, the oxaliplatin is insolution at a concentration of 2 mg/ml in pure water, as was recommendedin WO 96/04904. In the second, the oxaliplatin is in solution at aconcentration of 5 mg/ml in water buffered with oxalic acid. The twotypes of preparation, contained in sealed vials, were placed in anautoclave in order to undergo therein a wet heat finishing treatment, bysubjecting them to several heat cycles at a temperature of 121° C.

These known pharmaceutical preparations satisfy most of the qualitycriteria set by the health authorities, in particular that of sterility.

On the other hand, their uses are greatly limited due to their very lowconcentrations of oxaliplatin, making it necessary to store and handle alarge number of bottles or flexible bags and prohibiting the use ofparticularly suitable receptacles such as “prefilled” syringes or“multidose” bottles.

The present inventors have successfully managed to solve this problemengendered by the low concentrations of oxaliplatin, by making availablea stable pharmaceutical preparation of oxaliplatin for parenteraladministration, in which the oxaliplatin is in solution in a solvent ata concentration of at least 7 mg/ml. To do this, they found that the useof the solvent comprising a sufficient amount of at least onehydroxylated derivative chosen from 1,2-propanediol, glycerol, maltitol,sucrose and inositol made it possible to obtain preparations in whichthe concentration of oxaliplatin was well over 7 mg/ml.

However, they came up against some problems when it came to guaranteeingfor these preparations a high degree of sterility as required by thehealth authorities.

Specifically, in order to guarantee better safety of pharmaceuticalsterilization on an industrial scale, they preferred to use an endsterilization method involving heat sterilization, such as, for example,that described in WO 99/43355, rather than an aseptic filtration methodsuch as, for example, that mentioned in WO 96/04904.

In doing this, they noted that the use of this method, requiringbringing the preparations to be sterilized to a temperature of 121° C.in an autoclave, did not prove to be satisfactory.

Specifically, while the degree of sterilization was quite acceptable,the appearance of cloudiness, or even of blackish particles, was notedwhen the autoclave was opened at the end of the process and the bottlescontaining the preparations were released. It was then clear thatpreparations of oxaliplatin exhibiting such a physical appearance wouldhave been discarded from preparations made available to the patients.

The aim of the present invention is thus to make available a stablepharmaceutical preparation of oxaliplatin for parenteral administration,in which the oxaliplatin is in solution in a solvent at a concentrationsuch that it allows, firstly, a clear decrease in a number of bottles orflexible bags to be stored or handled and, secondly, the use of suitablereceptacles such as “prefilled” syringes or “multidose” bottles, whileat the same time satisfying the criteria required by the healthauthorities for the approval of pharmaceutical liquid preparations, suchas a high degree of sterility and a clear appearance free of solidparticles.

To this effect, the present invention relates to a stable pharmaceuticalpreparation of oxaliplatin for parenteral administration, intended to beinfused or injected, in which the oxaliplatin is in solution in asolvent at a concentration of at least 7 mg/ml, and which has beensubjected to an operation of wet heat treatment with steam in thesaturation state and under pressure at a high temperature not exceeding110° C.

Preferably, said solution has been subjected to an operation of wet heattreatment at a high temperature of between 110° C. and approximately 70°C. More preferably, this high temperature is approximately 80° C.

Preferably, said operation of wet heat treatment is carried out in thecourse of at least two cycles composed of a phase of heating at saidhigh temperature and then a phase of returning to and standing atambient temperature. More preferably, the phase of heating at the hightemperature lasts approximately 30 minutes and the phase of returning toand standing at ambient temperature lasts approximately 24 hours.

Preferably, the solvent of said solution containing the oxaliplatincomprises a sufficient amount of at least one hydroxylated derivativechosen from 1,2-propanediol, glycerol, maltitol, sucrose and inositol.More preferably, said solvent also comprises water.

The present invention also relates to a method for obtaining saidpreparation, using an operation of wet heat treatment with steam in thesaturation state and under pressure in an autoclave at high temperaturenot exceeding 110° C.

More precisely, this method comprises, prior to said wet heat treatmentoperation, the implementation of the following steps:

a) bringing an amount of oxaliplatin into contact, at a temperature lessthan 80° C., with a sufficient amount of said solvent in order to obtaina concentration of oxaliplatin of at least 7 mg/ml; and

b) establishing the mixture obtained in step a) at a temperature ofbetween 15° C. and 30° C.

Preferably, said wet heat treatment operation comprises at least twocycles composed of a phase of heating at said high temperature, and thena phase of returning to and standing at ambient temperature. Morepreferably, the phase of heating at the high temperature lastsapproximately 30 minutes, and the phase of returning to and standing atambient temperature lasts approximately 24 hours.

A specialist, realizing all the advantages of this method of production,will be able to apply each of its operation to any system of asepticfilling with liquid pharmaceutical preparations which is usually foundin the pharmaceutical industry, by adjusting each of the parametersmentioned to their most advantageous values, within their indicatedvalue ranges.

Thus, the specialist will prepare a filling solution in which theoxaliplatin is at a concentration of at least 7 mg/ml in the appropriatesolvent. He or she will then fill the appropriate sterilizedreceptacles, on a continuous or batch filling system, preferably underan atmosphere of an inert gas. These receptacles will, depending on thecase, be closed with a stopper or sealed, and then placed in anautoclave in order to undergo therein the operations of wet heattreatment with steam in the saturation state and under pressure in anautoclave at a high temperature not exceeding 110° C.

The invention, and its advantages, will be described hereinafter usingthe following examples:

EXAMPLE 1 Preparation of Solutions Containing Oxaliplatin at aConcentration of 10 mg/ml

In the laboratory, an oxaliplatin powder (250 mg) is placed in a 50 mlreceptacle graduated at 25 ml. One of the co-solvents chosen from1,2-propanediol, glycerol and maltitol, respectively, is introduced intothe receptacle at the same time as or prior to the addition of water tomake the volume up to 25 ml, according to the correspondingvolume/volume or weight/volume ratios as indicated in the varioustables.

Two other co-solvents, namely sucrose and inositol, were also used andresults identical to those described in the examples were obtained.

The mixtures obtained are, where appropriate, brought to a temperaturenot exceeding 80° C. and to atmospheric pressure in order to finish thecomplete dissolution of the oxaliplatin.

After returning to ambient temperature, namely approximately 20° C., aclarifying filtration operation is optionally carried out in order toensure clarity.

EXAMPLE 2 Comparative Test for Treatment at a Temperature ofApproximately 121° C.

The mixtures as obtained by applying the method described in example 1,and according to the relative amounts indicated in table 1, weresubjected to an operation of wet heat treatment at a temperature of 121°C. in an autoclave according to the methods well known to a specialist.

The results observed at the end of the treatment, after returning toambient temperature, are described in table 1.

TABLE 1 Active substance Oxaliplatin Oxaliplatin OxaliplatinConcentration 10 mg/ml 10 mg/ml 10 mg/ml Solvent 1,2-propanediol/ 85%glycerol/ maltitol/ water water water 50/50 (V/V) 50/50 (V/V) 50% (m/V)Heating 121° C. ± 2 121° C. ± 2 121° C. ± 2 temperature 30 min 30 min 30min and time Observations presence of presence of presence of blackprecipitate black precipitate black precipitateAt a temperature of 121° C., the appearance of a water-insoluble blackprecipitate is observed.

EXAMPLE 3 Comparative Test for Treatment at Temperatures ofApproximately 120° C. and of Approximately 110° C.

Various solutions of oxaliplatin at a concentration of 10 mg/ml,obtained as previously, and degassed beforehand with argon, weresubjected to operations of wet heat treatment at temperatures of 120° C.and 110° C., respectively.

The results observed at the end of the treatment, after returning toambient temperature, are described in tables 2 and 3.

TABLE 2 Active substance Oxaliplatin Oxaliplatin OxaliplatinConcentration 10 mg/ml 10 mg/ml 10 mg/ml Solvent 1,2-propanediol/ 85%glycerol/ maltitol/ degassed water water water with argon 20/20 (V/V)20/20 (V/V) 50% (m/V) Heating 120° C. ± 2 120° C. ± 2 120° C. ± 2temperature 150 min 150 min 150 min and time Observation presence ofpresence of presence of after storage black precipitate blackprecipitate black precipitate

TABLE 3 Active substance Oxaliplatin Oxaliplatin OxaliplatinConcentration 10 mg/ml 10 mg/ml 10 mg/ml Solvent 1,2-propanediol/ 85%glycerol/ maltitol/ degassed water water water with argon 20/20 (V/V)20/20 (V/V) 50% (m/V) Heating 110° C. ± 2 110° C. ± 2 110° C. ± 2temperature 120 min 120 min 120 min and time Observation presence ofpresence of presence of after storage black precipitate blackprecipitate black precipitate

At the respective temperatures of 120° C. and 110° C., the appearance ofa water-insoluble black precipitate is observed.

EXAMPLE 4 Comparative Test for Treatment of a Solution in aSupersaturated State, at a Temperature of 120° C.

A supersaturated aqueous solution of oxaliplatin, containing 10 mg ofoxaliplatin per 10 mg of water, was prepared without adding aco-solvent, by subjecting it to a temperature of approximately 80° C. atatmospheric pressure for a few minutes.

After returning to ambient temperature, this preparation was subjectedto an operation of wet heating at a temperature of 120° C.

The results are described in table 4.

TABLE 4 Active substance Oxaliplatin Concentration 10 mg/ml Solventwater for injectable preparation Heating temperature 120° C. ± 2 andtime 90 min Observation after storage presence of black precipitate

At the temperature of 120° C., the appearance of a water-insoluble blackprecipitate is observed.

EXAMPLE 5 Test for Treatment at Temperatures of Approximately 80° C. and70° C.

Solutions of oxaliplatin at concentrations of, respectively, 10 mg/mland 12 mg/ml, containing one of the following hydroxylated derivatives:1,2-propanediol, glycerol and maltitol, were subjected to an operationof wet heat treatment at respective temperatures of 70° C. and 80° C.

The results observed 24 hours after the end of the treatment, and areturn to ambient temperature, are described in table 5.

TABLE 5 Active substance Oxaliplatin Oxaliplatin Oxaliplatin OxaliplatinConcentration 10 mg/ml 10 mg/ml 10 mg/ml 12 mg/ml Solvent1,2-propanediol/ 85% glycerol/ maltitol/ maltitol/ water water waterwater 50/50 (V/V) 50/50 (V/V) 50% (m/V) 30% (m/V) Heating 70° C. ± 2 70°C. ± 2 70° C. ± 2 80° C. ± 2 temperature 30 min 30 min 30 min 30 min andtime Observatios complete complete complete complete solubilization ofsolubilization of solubilization of solubilization of the substance. thesubstance. the substance. the substance. No presence of No presence ofNo presence of No presence of precipitate. precipitate. precipitate.precipitate. Solution has Solution has Solution has Solution has clearclear clear clear appearance appearance appearance appearance

At respective temperatures of 70° C. and 80° C., the appearance of awater-insoluble black precipitate is not observed.

EXAMPLE 6 Test for Treatment of a Solution in the Supersaturated State,at Temperatures of Approximately 80° C.

An aqueous solution of oxaliplatin as prepared in example 4 wassubjected to an operation of wet heating at a temperature of 80° C. Theresults are described in table 6.

TABLE 6 Active substance Oxaliplatin Concentration 10 mg/ml Solventwater for injectable preparation Heating temperature and time 80° C. ± 230 min Observation after storage no presence of precipitate solution hasa clear appearanceAt the temperature of 80° C., no precipitate was observed.

EXAMPLE 7 Operation Involving Sterilization of Solutions of Oxaliplatinat a Concentration of 10 mg/ml by Wet Heat Treatment at a Temperature of80° C.

Various solutions of oxaliplatin at a concentration of 10 mg/ml,obtained using the method described in example 1 and by applying therelative amounts of various constituents as indicated in table 7, wereprepared.

They were then subjected to operations of wet heat sterilization bycarrying out three successive cycles of heating at a temperature of 80°C., followed by a return to an ambient temperature of approximately 20°C. The respective durations of the various phases of these cycles areindicated in table 7.

The solutions thus treated were kept, before observation, atrefrigerator temperature for 72 hours. The results are described intable 7.

TABLE 7 Active substance Oxaliplatin Oxaliplatin OxaliplatinConcentration 10 mg/ml 10 mg/ml 10 mg/ml Solvent 1,2-propanediol/ 85%glycerol/ maltitol/ water for water for water for injectable injectableinjectable preparation preparation preparation 50/50 (V/V) 50/50 (V/V)50% (m/V) Heating 80° C. ± 2 80° C. ± 2 80° C. ± 2 temperature 30 min 30min 30 min and time Time standing 24 h 24 h 24 h at approx. 20° C.Heating 80° C. ± 2 80° C. ± 2 80° C. ± 2 temperature 30 min 30 min 30min and time Time standing 24 h 24 h 24 h at approx. 20° C. Heating 80°C. ± 2 80° C. ± 2 80° C. ± 2 temperature 30 min 30 min 30 min and timeObservations complete complete complete solubilization of solubilizationof solubilization of the substance. No the substance. No the substance.No presence of presence of presence of precipitate. precipitate.precipitate. Solution has a Solution has a Solution has a clearappearance clear appearance clear appearance

At the end of each of the sterilizing treatments, a sterilization testwas carried out on each one of the preparations, according to theprotocol recommended in chapter 2.6.1. STERILITY of the EuropeanPharmacopoeia, 3rd edition, applying the membrane filtration method.

It was found that all the results were satisfactory. No contaminatingtrace of microorganisms was found.

From the preceding results, it results that pharmaceutical preparationsof oxaliplatin for parenteral administration, at a concentration ofgreater than or equal to 7 mg/ml, can be obtained, while being sterileand free of insoluble black precipitate, through sterilization bycarrying out successive heating operations at temperatures of 80° C.

1. A stable pharmaceutical preparation of oxaliplatin for parenteraladministration, in which the oxaliplatin is in solution in a solvent ata concentration of at least 7 mg/ml, and wherein the solution ofoxaliplatin has been subjected to an operation of wet heat treatmentwith steam in the saturation state and under pressure at a temperaturenot exceeding 110° C., and wherein the solvent of said solution whichcontains the oxaliplatin comprises a sufficient amount of at least onehydroxylated derivative chosen from 1,2-propanediol, glycerol, maltitol,sucrose and inositol.
 2. The stable pharmaceutical preparation ofoxaliplatin as claimed in claim 1, characterized in that said solutionhas been subjected to an operation of wet heat treatment at atemperature of between 110° C. and about 70° C.
 3. The stablepharmaceutical preparation of oxaliplatin as claimed in claim 1,characterized in that said solution has been subjected to an operationof wet heat treatment at a temperature of about 80° C.
 4. The stablepharmaceutical preparation of oxaliplatin as claimed in claim 1,characterized in that said wet heat treatment operation is carried outin the course of at least two cycles composed of a phase of heating atsaid temperature and then a phase of returning to aid standing atambient temperature.
 5. The stable pharmaceutical preparation ofoxaliplatin as claimed in claim 4, characterized in that said phase ofheating at the temperature lasts about 30 minutes and the phase ofreturning to and standing at ambient temperature lasts about 24 hours.6. The stable pharmaceutical preparation of oxaliplatin as claimed inclaim 1, characterized in that said solvent also comprises water.
 7. Amethod for obtaining a stable pharmaceutical preparation of oxaliplatinfor parenteral administration, in which the oxaliplatin is in solutionin a solvent at a concentration of at least 7 mg/ml, comprisingdissolving oxaliplatin in a solvent comprising a sufficient amount of atleast one hydroxylated derivative chosen from 1,2-propanediol, glycerol,maltitol, sucrose and inositol, and subjecting the solution to anoperation of wet heat treatment with steam in the saturation state andunder pressure at a temperature not exceeding 110° C.
 8. The method asclaimed in claim 7, which also comprises, prior to said wet heattreatment operation, the implementation of the following steps: a)bringing an amount of oxaliplatin into contact, at a temperature lessthan 80° C., with a sufficient amount of said solvent in order to obtaina concentration of oxaliplatin of at least 7 mg/ml; and b) establishingthe mixture obtained in step a) at a temperature of between 15° C. and30° C.